Association of VDR gene variant rs2228570-FokI with gestational diabetes mellitus susceptibility in Arab women.

Gestational diabetes mellitus (GDM) has been linked with adverse pregnancy outcomes. Vitamin D receptor (VDR) gene variants have been associated with diabetes mellitus susceptibility and related complications. This study assessed the association between VDR gene polymorphism (rs2228570) and GDM risk among pregnant Arab women. A total of 368 pregnant Saudi women who were screened for GDM at 24-28 weeks of gestation and genotyped for the VDR gene variant (rs2228570) were included in this cross-sectional study. Circulatory insulin levels, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and vitamin D (25(OH)D) were measured. There were 108 women with GDM and 260 women without GDM. The genotype frequency of women with GDM was CC 60.2 %, CT 33.3 %, TT 6.9 %, and CT + TT 39.8 %; for non-GDM women, were CC 61.1 %, CT 31.5 %, TT 6.9 %, and CT + TT 38.4 %. No association was found between the VDR gene variant (rs2228570-FokI) and GDM susceptibility after adjustment for covariates. Serum 25(OH)D had a significant inverse association with FBG (r = -0.49, p = 0.01) and HbA1c (r = -0.45, p = 0.03) among carriers of the TT-genotype. Furthermore, a significant inverse correlation was observed between serum 25(OH)D and HOMA-ß (r = -0.20, p = 0.035) in individuals with the T-allele. Among pregnant Saudi women, glycemic indices appear to be influenced by vitamin D, suggesting a possible role it may play in mitigating the metabolic changes associated with GDM, particularly among individuals with specific genetic backgrounds. In our study population, rs2228570-FokI did not appear to be a significant contributor to GDM risk.

Pharmacological p38 MAPK inhibitor SB203580 enhances AML stem cell line KG1a chemosensitivity to daunorubicin by promoting late apoptosis, cell growth arrest in S-phase, and miR-328-3p upregulation.

Acute myeloid leukaemia (AML) is characterized by uncontrolled proliferation of myeloid progenitor cells and impaired maturation, leading to immature cell accumulation in the bone marrow and bloodstream, resulting in hematopoietic dysfunction. Chemoresistance, hyperactivity of survival pathways, and miRNA alteration are major factors contributing to treatment failure and poor outcomes in AML patients. This study aimed to investigate the impact of the pharmacological p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on the chemoresistance potential of AML stem cell line KG1a to the therapeutic drug daunorubicin (DNR). KG1a and chemosensitive leukemic HL60 cells were treated with increasing concentrations of DNR. Cell Titer-Glo®, flow cytometry, phosphokinase and protein arrays, Western blot technology, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were employed for assessment of cell viability, half-maximal inhibitory concentration (IC50) determination, apoptotic status detection, cell cycle analysis, apoptosis-related protein and gene expression monitoring. Confocal microscopy was used to visualize caspase and mitochondrial permeability transition pore (mPTP) activities. Exposed at various incubation times, higher DNR IC50 values were determined for KG1a cells than for HL60 cells, confirming KG1a cell chemoresistance potential. Exposed to DNR, late apoptosis induction in KG1a cells was enhanced after SB203580 pretreatment, defined as the combination treatment. This enhancement was confirmed by increased cleavage of poly(ADP-ribose) polymerase, caspase-9, caspase-3, and augmented caspase-3/-7 and mPTP activities in KG1a cells upon combination treatment, compared to DNR. Using phosphokinase and apoptosis protein arrays, the combination treatment decreased survival Akt phosphorylation and anti-apoptotic Bcl-2 expression levels in KG1a cells while increasing the expression levels of the tumor suppressor p53 and cyclin-dependent kinase inhibitor p21, compared to DNR. Cell cycle analysis revealed KG1a cell growth arrest in G2/M-phase caused by DNR, while combined treatment led to cell growth arrest in S-phase, mainly associated with cyclin B1 expression levels. Remarkably, the enhanced KG1a cell sensitivity to DNR after SB203580 pretreatment was associated with an increased upregulation of miR-328-3p and slight downregulation of miR-26b-5p, compared to DNR effect. Altogether, these findings could contribute to the development of a new therapeutic strategy by targeting the p38 MAPK pathway to improve treatment outcomes in patients with refractory or relapsed AML.

Melatonin delivered in solid lipid nanoparticles ameliorated its neuroprotective effects in cerebral ischemia.

The current study explores the potential of melatonin (MLT)-loaded solid lipid nanoparticles (MLT-SLNs) for better neuroprotective effects in ischemic stroke. MLT-SLNs were prepared using lipid matrix of palmityl alcohol with a mixture of surfactants (Tween 40, Span 40, Myrj 52) for stabilizing the lipid matrix. MLT-SLNs were tested for physical and chemical properties, thermal and polymorphic changes, in vitro drug release and in vivo neuroprotective studies in rats using permanent middle cerebral artery occlusion (p-MCAO) model. The optimized MLT-SLNs showed particle size of ∼159 nm, zeta potential of -29.6 mV and high entrapment efficiency ∼92%. Thermal and polymorphic studies showed conversion of crystalline MLT to amorphous form after its entrapment in lipid matrix. MLT-SLNs displayed a sustained release pattern compared to MLT dispersion. MLT-SLNs significantly enhanced the neuroprotective profile of MLT ascertained by reduced brain infarction, recovered behavioral responses, low expression of inflammatory markers and improved oxidation protection in rats. MLT-SLNs also showed reduced hepatotoxicity compared to p-MCAO. From these outcomes, it is evidenced that MLT-SLNs have improved neuroprotection as compared to MLT dispersion and thereby present a promising approach to deliver MLT to the brain for better therapeutic outcomes in ischemic stroke.

Achillea fragrantissima (Forssk.) Sch.Bip Flower Dichloromethane Extract Exerts Anti-Proliferative and Pro-Apoptotic Properties in Human Triple-Negative Breast Cancer (MDA-MB-231) Cells: In Vitro and In Silico Studies.

The aggressive triple-negative breast cancer (TNBC) is a challenging disease due to the absence of tailored therapy. The search for new therapies involves intensive research focusing on natural sources. Achillea fragrantissima (A. fragrantissima) is a traditional medicine from the Middle East region. Various solvent extracts from different A. fragrantissima plant parts, including flowers, leaves, and roots, were tested on TNBC MDA-MB-231 cells. Using liquid chromatography, the fingerprinting revealed rich and diverse compositions for A. fragrantissima plant parts using polar to non-polar solvent extracts indicating possible differences in bioactivities. Using the CellTiter-Glo™ viability assay, the half-maximal inhibitory concentration (IC50) values were determined for each extract and ranged from 32.4 to 161.7 µg/mL. The A. fragrantissima flower dichloromethane extract had the lowest mean IC50 value and was chosen for further investigation. Upon treatment with increasing A. fragrantissima flower dichloromethane extract concentrations, the MDA-MB-231 cells displayed, in a dose-dependent manner, enhanced morphological and biochemical hallmarks of apoptosis, including cell shrinkage, phosphatidylserine exposure, caspase activity, and mitochondrial outer membrane permeabilization, assessed using phase-contrast microscopy, fluorescence-activated single-cell sorting analysis, Image-iT™ live caspase, and mitochondrial transition pore opening activity, respectively. Anticancer target prediction and molecular docking studies revealed the inhibitory activity of a few A. fragrantissima flower dichloromethane extract-derived metabolites against carbonic anhydrase IX, an enzyme reported for its anti-apoptotic properties. In conclusion, these findings suggest promising therapeutic values of the A. fragrantissima flower dichloromethane extract against TNBC development.

Angiotensin II Exaggerates SARS-CoV-2 Specific T-Cell Response in Convalescent Individuals following COVID-19.

Dysregulation of renin-angiotensin systems during coronavirus disease 2019 (COVID-19) infection worsens the symptoms and contributes to COVID-19 severity and mortality. This study sought to investigate the effect of exogenous angiotensin II (Ang-II) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cells response in recovered COVID-19 patients. Human peripheral blood mononuclear cells (PBMCs) were treated with Ang II and then stimulated with a SARS-CoV-2 peptide pool. T-cell responses were measured using flow cytometry, while enzyme-linked immunosorbent assay (ELISA) and intracellular cytokine staining (ICS) assays determined functional capability and polarization. Additionally, the relative level of protein phosphorylation was measured using a phosphokinase array. Our results showed that Ang II treatment significantly increased the magnitude of SARS-CoV-2-specific T-cell response in stimulated PBMCs with a SARS-CoV-2 peptide pool. Moreover, the phosphorylation levels of numerous proteins implicated in cardiovascular diseases, inflammation, and viral infection showed significant increases in the presence of Ang II. The mitogenic stimulation of PBMCs after Ang II and SARS-CoV-2 peptide pool stimulation showed functional polarization of T-cells toward Th1/Th17 and Th17 phenotypes, respectively. Meanwhile, ELISA showed increased productions of IL-1ß and IL-6 in Ang II-stimulated PBMCs without affecting the IL-10 level. To our knowledge, this study is the first to demonstrate that Ang II exaggerates SARS-CoV-2-specific T-cells response. Therefore, during COVID-19 infection, Ang II may aggravate the inflammatory response and change the immune response toward a more inflammatory profile against SARS-CoV-2 infection.

Insights Into the Role of Epigenetic Factors Determining the Estrogen Response in Estrogen-Positive Ovarian Cancer and Prospects of Combining Epi-Drugs With Endocrine Therapy.

Ovarian cancer is one of the most lethal malignancies. The population at the risk is continually on the rise due to the acquired drug resistance, high relapse rate, incomplete knowledge of the etiology, cross-talk with other gynecological malignancies, and diagnosis at an advanced stage. Most ovarian tumors are thought to arise in surface epithelium somehow in response to changes in the hormonal environment. Prolonged treatment with hormone replacement therapy (HRT) is also considered a contributing factor. Estrogens influence the etiology and progression of the endocrine/hormone-responsive cancers in a patient-specific manner. The concept of hormonal manipulations got attention during the last half of the 20th century when tamoxifen was approved by the FDA as the first selective estrogen receptor modulator (SERM). Endocrine therapy that has been found to be effective against breast cancer can be an option for ovarian cancer. It is now established that global changes in the epigenetic landscape are not only the hallmark of tumor development but also contribute to the development of resistance to hormone therapy. A set of functionally related genes involved in epigenetic reprogramming are controlled by specific transcription factors (TFs). Thus, the activities of TFs mediate important mechanisms through which epigenetic enzymes and co-factors modify chromatin for the worst outcome in a site-specific manner. Furthermore, the role of epigenetic aberrations involving histone modifications is established in ovarian cancer pathogenesis. This review aims to provide insights on the role of key epigenetic determinants of response as well as resistance to the hormone therapy, the current status of research along with its limitations, and future prospects of epigenetic agents as biomarkers in early diagnosis, prognosis, and personalized treatment strategies. Finally, the possibility of small phytoestrogenic molecules in combination with immunotherapy and epi-drugs targeting ovarian cancer has been discussed.

A Time-Course Evaluation of DNA Damage and Neurotoxicity Induced by PEGylated Graphene Oxide Nanoparticle in Swiss Albino Mice.

PEGylated graphene oxide nanoparticle (PEG-nGO) has been commonly used as a carrier for therapeutic drugs and vaccines, because of its unique properties, such as high solubility, more stability and increased biocompatibility in physiological solutions. This study aimed to examine the DNA damage and neurotoxicity in young mice after up to 4 h of the treatment with PEG-nGO. A single dose (5 mg/kg) of intravenous injection was administered through the tail vein of adult mice. Total genomic DNA was isolated from the control and treated animals after 1 h, 2 h, and 4 h of treatments and examined for DNA damage by diphenyl assay, DNA fragmentation Assay, and FTIR (Fourier transform infrared) techniques. DNA damage studies indicated DNA fragmentation after 1 h and 2 h of treatments followed by recovery at 4 h. FTIR analysis further supported these results and showed a detailed molecular effect of the treatments that caused single and double-strand DNA breaks at 1 to 2 h after the treatments and indicated DNA damage response and recovery at 4 h. Histopathology showed neuronal apoptosis and lesions in the brain after 1 to 2 h and invasion of inflammatory response and chromatolysis after 4 h. PEG-nGO caused immediate DNA damage and cytotoxicity to the brain and its future use as a drug carrier should be considered with caution.

Association of Alzheimer's Disease with Genetic Variants of Apolipoprotein E, Clusterin, TNF-α, and IL-6 Among Elderly Saudis.

BACKGROUND: In the wake of the warning by WHO that the prevalence of dementia may have a rise of 125% in the Middle East by 2050, identification of the genetic risk factors in Arab populations is urgent. OBJECTIVES: To investigate the association of Single Nucleotide Polymorphisms (SNPs) in apolipoprotein E (ApoE), clusterin (CLU), tumor necrotic factor- α (TNF-α) and interleukin-6 (IL-6) genes, with risk of Alzheimer's disease (AD) in Saudi Arabian participants. METHODS: A total of 42 Saudi AD patients and 23 age-matched control participants were genotyped for eight SNPs: rs429358, rs7412 (ApoE); rs11136000, rs1532278 (CLU); rs1800629, rs1799724 (TNF-α) and rs1800796, rs1800795(IL-6), by RT-PCR using the TaqMan assay. Serum concentrations of amyloid beta peptide 1-40(Aß1-40), amyloid beta peptide 1-42(Aß1- 42), CLU and some other biochemical markers were measured. RESULTS: A significant increase (p=0.004) in the serum CLU level was detected in the AD group (340.4 ± 74.6) compared with control group (265.0 ± 80.9). For rs1532278 (CLU), genotype GA was significantly higher in AD patients (57.1%) than in the control participants (26.1%), [p=0.024, OR = 4.00, 95% CI (1.20-13.28)]. For the ApoE SNP rs7412, 40.4% of patients carried a TT genotype, whereas it was completely absent in the controls [p = 0.020, OR = 30.53, 95% CI (1.73 - 540.05)].For rs429358 (ApoE), patients showed a significantly increased frequency of the TC genotype [p = 0.006, OR = 9.33, 95% CI (1.89-46.19)] and TT [p = 0.045, OR = 19.76, 95% CI (1.07-366.0)] genotype than controls. AD patients with CC genotype for ApoE rs429358 had significantly lower levels of Aß1-40 (p=0.04) in AD patients than controls. Carriers of genotype GG for rs1800629 (TNF-α) showed significantly higher levels of serum IL-6 (p = 0.04) in AD patients. CONCLUSION: Genetic variants in ApoE and CLU may influence susceptibility to AD among Saudi Arabian participants.

Angiogenin Levels and Their Association with Cardiometabolic Indices Following Vitamin D Status Correction in Saudi Adults.

Angiogenin (ANG), a multifunctional protein known to induce blood vessel formation, is a potential biomarker for cardiovascular diseases; however, whether it is affected by vitamin D supplementation is not known. This interventional study in vitamin D-deficient Saudi adults was designed to investigate it. A total of 100 vitamin D-deficient Saudi adults aged 30-50 years were randomly selected to undergo 6-month vitamin D supplementation. Circulating levels of fasting glucose, lipids, vitamin D, apolipoproteins (AI, AII, B, CI, CII, CIII, E, and H), and ANG were measured using commercially available assays at baseline and after six months. Overall, vitamin D levels increased significantly post intervention. With this, levels of apo-CIII and apo-E significantly increased (p-values of 0.001 and 0.009, respectively) with a significant parallel decrease in apo-B (p = 0.003). ANG levels were significantly positively associated with most apolipoproteins and inversely correlated with HDL-cholesterol. Post intervention, the changes in ANG levels were positively correlated with apo-E (r = 0.32; p < 0.01 in all subjects and r = 0.40; p < 0.05 in males). Vitamin D supplementation may modestly affect ANG levels. The association observed between ANG and apo-E is worthy of further investigation since both biomarkers have been linked to neurodegenerative disorders.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.

The Effect of Local Renin Angiotensin System in the Common Types of Cancer.

The Renin Angiotensin System (RAS) is a hormonal system that is responsible for blood pressure hemostasis and electrolyte balance. It is implicated in cancer hallmarks because it is expressed locally in almost all of the body's tissues. In this review, current knowledge on the effect of local RAS in the common types of cancer such as breast, lung, liver, prostate and skin cancer is summarised. The mechanisms by which RAS components could increase or decrease cancer activity are also discussed. In addition to the former, this review explores how the administration of AT1R blockers and ACE inhibitors drugs intervene with cancer therapy and contribute to the outcomes of cancer.

Enhanced Accumulation of Cisplatin in Ovarian Cancer Cells from Combination with Wedelolactone and Resulting Inhibition of Multiple Epigenetic Drivers.

PURPOSE: Cisplatin resistance is a major concern in ovarian cancer treatment. The aim of this study was to investigate if wedelolactone could perform better in resistant ovarian cancer cells when used in combination with cisplatin. METHODS: Growth inhibitory potential of wedelolactone and cisplatin was investigated through MTT reduction assay in ovarian cancer cell lines including A2780 (sensitive), A2780cisR (cisplatin resistant) and A2780ZD0473R. Resistance factor (RF) of drugs was determined in these three cell lines. Combination index (CI) was calculated as a measure of combined drug action. Effect of this combination on changes in the cellular accumulation of platinum levels and platinum-DNA binding was also determined in vitro using AutoDock Vina while the effect of wedelolactone on inhibition of possible key culprits of resistance including Chk1, CD73, AT tip60, Nrf2, Brd1, PCAF, IGF1, mTOR1 and HIF2α was investigated in silico. RESULTS: Cisplatin and wedelolactone showed a dose-dependent growth inhibitory effect. RF value of wedelolactone was 1.1 in the case of A2780cisR showing its potential to bring more cell death in cisplatin-resistant cells. CI values were found to vary showing antagonistic to additive outcomes. Additive effect was observed for all sequences of administration (0/0, 0/4 and 4/0 h) in A2780cisR. Enhanced cellular accumulation of cisplatin was observed in parent and resistant cells on combination. Docking results revealed that among the selected oncotargets, Chk1, CD73, Nrf2, PCAF and AT tip60 were more vulnerable to wedelolactone than their respective standard inhibitors. CONCLUSION: These findings have shown that additive outcome of drug combination in A2780cisR and raised levels of platinum accumulation followed a clear pattern. This observation indicates that the presence of wedelolactone might have contributed to sensitize A2780cisR. However, in silico results point to the possible effects of this compound on epigenetic factors involving tumor microenvironment, epithelial mesenchymal transition, and immune-checkpoint kinases.

Enhanced neuroprotective and antidepressant activity of curcumin-loaded nanostructured lipid carriers in lipopolysaccharide-induced depression and anxiety rat model.

The present study aims to develop curcumin-loaded nanostructured lipid carriers (CUR-NLCs) and investigate their neuroprotective effects in lipopolysaccharide (LPS)-induced depression and anxiety model. Nanotemplate engineering technique was used to prepare CUR-NLCs with Compritol 888 ATO and oleic acid as solid and liquid lipid, respectively. Poloxamer 188, Tween 80 and Span 80 were used as stabilizing agents for solid-liquid lipid core. The physicochemical parameters of CUR-NLCs were determined followed by in vitro drug release and in vivo neuroprotective activity in rats. The optimized CUR-NLCs demonstrated nanometric particle size of 147.8 nm, surface charge of -32.8 mV and incorporation efficiency of 91.0%. CUR-NLCs showed initial rapid followed by a sustained drug release reaching up to 73% after 24 h. CUR-NLCs significantly elevated struggling time and decreased immobility time in forced swim and tail suspension tests. A substantial increase in time spent and number of entries into the light and open compartments was observed in light-dark box and elevated plus maze models. CUR-NLCs improved the tissue architecture and suppressed the expression of p-NF-κB, TNF-α and COX-2 in brain tissues from histological and immunohistochemical analysis. CUR-NLCs improved the neuroprotective effect of curcumin and can be used as a potential therapeutics for depression and anxiety.

Contribution of Attenuation of TNF-α and NF-κB in the Anti-Epileptic, Anti-Apoptotic and Neuroprotective Potential of Rosa webbiana Fruit and Its Chitosan Encapsulation.

Rosa webbiana L. (Rosaceae) is one of the least reported and most understudied members of this family. It is native to the Himalayan regions of Pakistan and Nepal. The anti-convulsant effect of n-hexane extract of fruit of Rosa webbiana was investigated in a pentylenetetrazole (PTZ)-induced animal model of epilepsy. Male Sprague-Dawley rats were divided into six groups (n = 7) including control, PTZ (40 mg/kg), diazepam (4 mg/kg) and n-hexane extract (at 50, 150 and 300 mg/kg). Convulsive behavior was observed and resultant seizures were scored, animals sacrificed and their brains preserved. Chitosan nanoparticles were prepared using the ionic gelation method and characterized by UV-analysis, zeta potential and Fourier transform infrared spectroscopy (FTIR). The effects of all the treatments on the expression of phosphorylated cytokine tumor necrosis factor α (p-TNF-α) and phosphorylated transcription factor nuclear factor kappa B (p-NF-κB) expression in the cortex and hippocampus of the brains of treated rats were studied through enzyme linked immunosorbent assay (ELISA) and morphological differences and surviving neuronal number were recorded through hematoxylene and eosin (H&E) staining. Significant changes in seizures score and survival rate of rats were observed. Downregulation of neuro-inflammation, p-TNF-α and p-NF-κB was evident. Gas Chromatography-Mass Spectrometry (GC-MS) analysis of this fraction showed multiple constituents of interest, including esters, alkanes and amines.

Classical and Counter-Regulatory Renin-Angiotensin System: Potential Key Roles in COVID-19 Pathophysiology.

In the current COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 uses angiotensin-converting enzyme-2 (ACE-2) receptors for cell entry, leading to ACE-2 dysfunction and downregulation, which disturb the balance between the classical and counter-regulatory renin-angiotensin system (RAS) in favor of the classical RAS. RAS dysregulation is one of the major characteristics of several cardiovascular diseases; thus, adjustment of this system is the main therapeutic target. RAS inhibitors-particularly angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs)-are commonly used for treatment of hypertension and cardiovascular disease. Patients with cardiovascular diseases are the group most commonly seen among those with COVID-19 comorbidity. At the beginning of this pandemic, a dilemma occurred regarding the use of ACEIs and ARBs, potentially aggravating cardiovascular and pulmonary dysfunction in COVID-19 patients. Urgent clinical trials from different countries and hospitals reported that there is no association between RAS inhibitor treatment and COVID-19 infection or comorbidity complication. Nevertheless, the disturbance of the RAS that is associated with COVID-19 infection and the potential treatment targeting this area have yet to be resolved. In this review, the link between the dysregulation of classical RAS and counter-regulatory RAS activities in COVID-19 patients with cardiovascular metabolic diseases is investigated. In addition, the latest findings based on ACEI and ARB administration and ACE-2 availability in relation to COVID-19, which may provide a better understanding of the RAS contribution to COVID-19 pathology, are discussed, as they are of the utmost importance amid the current pandemic.

Dans l'actuelle pandémie de la COVID-19, le coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2) utilise les récepteurs de l'enzyme de conversion de l'angiotensine 2 (ECA-2) pour entrer dans les cellules, s'ensuit le dysfonctionnement et la régulation à la baisse de l'ECA-2, qui perturbent l'équilibre entre le système rénine-angiotensine (SRA) traditionnel et le SRA contre-régulateur en faveur du SRA traditionnel. La dysrégulation du SRA est l'une des caractéristiques principales des maladies cardiovasculaires. Par conséquent, l'ajustement de ce système est l'objectif thérapeutique principal. Les inhibiteurs du SRA, particulièrement les inhibiteurs de l'ECA (IECA) et les antagonistes des récepteurs de type 1 de l'angiotensine II (ARA), sont communément utilisés pour traiter l'hypertension et les maladies cardiovasculaires. Les patients atteints de maladies cardiovasculaires représentent le groupe le plus fréquemment observé parmi les patients atteints de comorbidités associées à la COVID-19. Au début de la pandémie, un dilemme à propos de l'utilisation des IECA et des ARA s'est posé, puisqu'ils aggravaient potentiellement la dysfonction cardiovasculaire et pulmonaire chez les patients atteints de la COVID-19. Des essais cliniques urgents issus de différents pays et hôpitaux ont montré qu'il n'y avait pas d'association entre le traitement par inhibiteurs du SRA et les complications liées à l'infection par la COVID-19 ou aux comorbidités. Néanmoins, la perturbation du SRA qui est associée à l'infection par la COVID-19 et le traitement potentiel dans ce champ restent à résoudre. Dans la présente revue, le lien entre la dysrégulation du SRA traditionnel et les activités contre-régulatrices du SRA chez les patients atteints de la COVID-19 qui ont des maladies cardiovasculaires métaboliques est étudié. De plus, nous nous penchons sur les plus récentes conclusions fondées sur l'administration des IECA et des ARA et la disponibilité de l'ECA2 en relation avec la COVID-19 pour offrir une meilleure compréhension de la contribution du SRA à la pathologie de la COVID-19, puisqu'ils sont de la plus haute importance dans le contexte de l'actuelle pandémie.

Therapeutic Potential of Vitamin D and Curcumin in an In Vitro Model of Alzheimer Disease.

BACKGROUND: Alzheimer disease is a progressive neurodegenerative disease, affecting a very high proportion of the aging population. Several studies have demonstrated that one of the main contributors to this disease is oxidative stress (OS), which causes peroxidation of protein, lipids, and DNA resulting in the formation of advanced glycosylated end products (AGE) in the brain tissues. These AGE are usually associated with the amyloid ß (Aß), which could further aggravate its toxicity and its clearance. Antioxidants counteract the deterioration caused by OS. OBJECTIVE: We aimed to evaluate the effect of vitamin D3 and curcumin on primary cortical neuronal cultures exposed to Aß1-42 toxicity for different time periods. METHODS: Primary cortical neuronal cultures were set up and exposed to Aß1-42 for up to 72 hours. Cell viability was studied by 3[4,5-dimethylthiazole-2-yl]-2,5-dipheyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Biochemical assays for OS such as lipid peroxidation, reduced Glutathione(GSH), Glutathione S-transferase (GST), catalase, and superoxide dismutase (SOD) were conducted. Sandwich enzyme-linked immunosorbent assay (ELISA) was used to study the neurotrophic growth factor (NGF) expression. RESULTS: Treatments with Aß1-42 caused an elevation in lipid peroxidation products, which were ameliorated in the presence of vitamin D3 and curcumin. Both enzymatic (GST, catalase, and SOD) and nonenzymatic antioxidants (reduced GSH) were raised significantly in the presence of vitamin D3 and curcumin, which resulted in the better recovery of neuronal cells from Aß1-42 treatment. Treatment with vitamin D3 and curcumin also resulted in the upregulation of NGF levels. CONCLUSIONS: This study suggests that vitamin D3 and curcumin can be a promising natural therapy for the treatment of Alzheimer disease.

Amelioration of thioacetamide-induced liver toxicity in Wistar rats by rutin.

This study was designed to evaluate the effect of rutin on hepatotoxicity induced by thioacetamide (TAA) in rats. Four groups of male Wistar rats consisting of six rats each were used: Group I: control group; Group II: rats receiving single injection of 300 mg kg-1 body weight of TAA intraperitoneally; Group III: rats administered rutin (10 mg kg-1 body weight) dissolved in saline orally for 2 weeks; and Group IV: rats administered rutin (10 mg kg-1 body weight) dissolved in saline orally for 2 weeks followed by TAA injection last day of second week. All groups were sacrificed after 24 h of treatment and hepatic toxicity was analyzed with respect to liver toxicity markers, liver DNA fragmentation, and histology of liver tissue. Administration of TAA in Wistar rats resulted in significant increase of hepatic markers, DNA fragmentation in the hepatocytes, and changes in histology. Pretreatment of rats with rutin before 2 weeks of TAA assault resulted in the complete reversal of TAA-mediated hepatic toxicity ( P < 0.0001 to P < 0.01) with concomitant restoration of DNA fragmentation. This study suggests rutin as a protective agent for restoration of toxicity caused by TAA.